Models of unregulated nitric oxide (NO) diffusion do not consistently account for the biochemistry of NO synthase (NOS)-dependent signaling in many cell systems. For example, endothelial NOS (eNOS) controls blood pressure, blood flow and oxygen delivery through its effect on vascular smooth muscle tone, but the regulation of these processes is not adequately explained by simple NO diffusion from endothelium to smooth muscle.
Control of arteriolar smooth muscle tone is central to regulation of blood pressure, blood flow and oxygen delivery. Nitric oxide (NO) synthase (NOS) in endothelial cells helps to regulate arteriolar tone by signaling smooth muscle relaxation across the myoendothelial junction (MEJ). However, substantial evidence suggests that simple, unregulated NO diffusion does not account for the physiology and biochemistry of NOS-dependent signaling.
Endothelial NOS modulates blood vessel diameter in response to both vasodilators and vasoconstrictors. For example, it is known that during arterial constriction NO from endothelium feeds back on smooth muscle to control the magnitude of the response to a vasoconstrictor (e.g., phenylephrine (PE)). Heme iron oxidation state affects the chemistry of NO-hemoglobin interactions.
There is a long felt need in the art for compositions and methods for regulating the tone of reactive vessels. The present invention satisfies these needs.